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WO2007146695A1 - Inhibiteurs oximyle acycliques de protéase de l'hépatite c - Google Patents

Inhibiteurs oximyle acycliques de protéase de l'hépatite c Download PDF

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Publication number
WO2007146695A1
WO2007146695A1 PCT/US2007/070481 US2007070481W WO2007146695A1 WO 2007146695 A1 WO2007146695 A1 WO 2007146695A1 US 2007070481 W US2007070481 W US 2007070481W WO 2007146695 A1 WO2007146695 A1 WO 2007146695A1
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WIPO (PCT)
Prior art keywords
substituted
cycloalkyl
cycloalkenyl
heteroaryl
aryl
Prior art date
Application number
PCT/US2007/070481
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English (en)
Inventor
Yat Sun Or
Ying Sun
Zhe Wang
Original Assignee
Enanta Pharmaceuticals, Inc.
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Application filed by Enanta Pharmaceuticals, Inc. filed Critical Enanta Pharmaceuticals, Inc.
Publication of WO2007146695A1 publication Critical patent/WO2007146695A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to novel hepatitis C virus (HCV) protease inhibitor compounds having antiviral activity against HCV and useful in the treatment of HCV infections. More particularly, the invention relates to novel acyclic oximyl HCV protease inhibitor compounds, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
  • HCV hepatitis C virus
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
  • HIV human immunodeficiency virus
  • anti-HC V therapeutics There are considerable barriers to the development of anti-HC V therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • NS3 hepatitis C non-structural protein-3
  • HCV is a flaviridae type RNA virus.
  • the HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • the HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, El and E2.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence. There are six non-structural proteins.
  • NS2 is a zinc- dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • the NS3-NS4A protease is responsible for cleaving four sites on the viral polyprotein.
  • the NS3-NS4A cleavage is autocatalytic, occurring in cis.
  • the remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans.
  • NS3 is a serine protease which is structurally classified as a chymotrypsin- like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus.
  • Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881
  • HCV protease inhibitors More relevant patent disclosures describing the synthesis of HCV protease inhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO 99/50230 (1999); US5861297 (1999); US publications 20050153877, 20050261200 and 20050065073.
  • the present invention relates to novel HCV protease inhibitor compounds, and pharmaceutically acceptable salts, esters, or prodrugs thereof, which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3- NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the present invention further relates to pharmaceutical compositions comprising the aforementioned compounds, salts, esters or prodrugs for administration to a subject suffering from HCV infection.
  • the present invention further features pharmaceutical compositions comprising a compound of the present invention (or a pharmaceutically acceptable salt, ester or prodrug thereof) and another anti-HCV agent, such as alpha-interferon, beta-interferon, ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor.
  • a pharmaceutical composition of the present invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition of the present invention.
  • Ri and R 2 are independently selected from the group consisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl; e) substituted heteroaryl; f) heterocyclic or substituted heterocyclic; g) -Ci-Cg alkyl, -C 2 -Cg alkenyl, or -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, or substituted -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C 3 -Ci 2 cycloalkyl, or -C 3 -Ci 2 cycloalkenyl; j) substituted -
  • R 3 and R 4 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl;
  • G is -E-R 3 , where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO 2 )NH or NHSO 2 ;
  • A is selected from the group consisting of R 5 , (CO)R 5 , (CO)OR 5 , (CO)NHR 5 , SO 2 R 5 , (SO 2 )OR 5 and SO 2 NHR 5 ;
  • R 5 is selected from the group consisting of: a) aryl; b) substituted aryl; c) heteroaryl; d) substituted heteroaryl; e) heterocyclic; f) substituted heterocyclic; g) -Ci-Cg alkyl, -C 2 -Cg alkenyl, or -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; h) substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, or substituted -C 2 -Cg alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) -C 3 -C 12 cycloalkyl, or -C 3 -Ci 2 cycloalkenyl; j) substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2
  • B is H or CH 3 ;
  • L and Z are independently selected from the group consisting of:
  • the present invention features pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • methods of treating a hepatitis C infection in a subject in need of such treatment with said pharmaceutical compositions are disclosed.
  • the present invention is a compound of formula I as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • the present invention relates to a compound of formula II, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Ri is not hydrogen .
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, and substituted -C 3 -C 12 cycloalkenyl.
  • A is selected from the group consisting of -C(O)-R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • L and Z can be independently selected from Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • G can be -0-R 3 , -NH-C(O)-R 3 , -NH-SO 2 -NH- R 3 or -NHSO 2 -R 3 , where R 3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted - C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-O-R 5 , where R 5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 - Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-NH-R 5 , where R 5 is -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO2-R3, where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-Rs, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 - C 12 cycloalkenyl.
  • Ri is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, substituted -C 1 -C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula III, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • A, G, L, R 1 , R 2 and Z are as previously defined in the first embodiment.
  • Ri and R 2 are not both hydrogen.
  • Ri and R 2 are independently selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -C 12 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 - Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl; or Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A can be selected from the group consisting of -C(O)-R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 -Cs alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-C 8 alkyl, -C 2 - C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted - C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • G can be -0-R 3 , -NH-C(O)- R 3 , -NH-SO 2 -NH-R 3 or -NHSO 2 -R 3 , where R 3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - C 12 cycloalkenyl.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 2 - Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 - Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-O-Rs, where Rs is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from Ci-Cg alkyl, substituted -Ci-C 8 alkyl, -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • A is -C(O)-O-Rs, where R5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-NH-R 5 , where R 5 is -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • Ri and R 2 taken together with the
  • each group is independently selected from halogen, hydroxy, nitro, cyano, amino, formyl, -Ci-Cgalkyl or -C 2 -Cgalkenyl, or -C 2 - Cgalkynyl.
  • Ri and R 2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from (1) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic, or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic each fused with one or more R 3 , where each R 3 is independently selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • A is -C(O)-R 5 , where R 5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • R 5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cg alkyl, - C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted - C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -C 8 alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is - NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Ri and R 2 taken together with the carbon
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -C r C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • V is absent, or V is CO, O, S, SO, SO 2 , NH, NCH 3 , or (CH 2 ) q ; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of: aryl; substituted aryl; heteroaryl; substituted heteroaryl; heterocyclic; substituted heterocyclic; and where A, G, L and Z are as previously defined in the first embodiment.
  • Xi-Xg are independently selected from CH and N and Xi-Xg can be further substituted when it is a CH
  • Y 1 -Y 3 are independently selected from CH, N, NH, S and O and Yi-Y 3 can be further substituted when it is CH or NH
  • V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A can be selected from the group consisting of -C(O)-R 5 , - C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -Cs-Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • G can be -0-R 3 , -NH-C(O)-R 3 , -NH-SO 2 -NH-R 3 or -NHSO 2 -R 3 , where R 3 is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • CH and N and Xi-X 8 can be further substituted when it is a CH
  • Yi-Y 3 are independently selected from CH, N, NH, S and O and Yi-Y 3 can be further substituted when it is CH or NH
  • V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A is -C(O)-O-R 5 , where R 5 is -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, - C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from Ci-C 8 alkyl, substituted -Ci-C 8 alkyl, -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • +&* ⁇ is selected from
  • W l I e I eIn X 1 -X 8 are independently selected from CH and N and X 1 -X 8 can be further substituted when it is a CH, and Y 1 -Y 3 are independently selected from CH, N, NH, S and O and Y 1 -Y 3 can be further substituted when it is CH or NH; V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A is -C(O)-O-R 5 , where R 5 is -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • L is selected from -C 1 -C 8 alkyl or substituted -C 1 -C 8 alkyl.
  • Z is selected from C 1 -C 8 alkyl, substituted -C 1 -C 8 alkyl,- C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • R 1 and R 2 taken together with the carbon atom to
  • X 1 -X 8 are independently selected from CH and N and X 1 -X 8 can be further substituted when it is a CH;
  • V is absent, CO, O, S, NH, or (CH 2 ) q , where q is 1, 2 or 3.
  • A is -C(O)-O- R 5 , where R 5 is -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • L is selected from -C 1 -C 8 alkyl or substituted -C 1 -C 8 alkyl.
  • Z is selected from C 1 -C 8 alkyl, substituted -C 1 -C 8 alkyl, -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is - NHSO 2 -R 3 , where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl. In a most preferred example, R 1 and R 2 taken together with the carbon atom
  • A is -C(O)-O-R 5 , where R 5 is - C3-C12 cycloalkyl or substituted -C 3 -C 12 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from Ci-Cg alkyl, substituted -Ci-Cg alkyl, -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO2-R3, where R 3 is selected from -C 3 -C 12 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula
  • X 1 -X 4 are independently selected from CO, CH, NH, O and N; where X 1 -X 4 can be further substituted when any one of X 1 -X 4 is a CH or NH; where R 6 and R 7 are independently R 3 , where R 3 is independently selected from the group consisting of:
  • R ⁇ and R 7 can be independently selected from halogen, oxo, thioxo, nitro, cyano, -OR 3 , -SR 3 , -NR 3 R 4 , -SOR 3 , -SO 2 R 3 , -NHSO 2 R 3 , -SO 2 NHR 3 , -COR 3 , -CO 2 R 3 , (CO)NHR 3 , -OCOR 3 , OCONHR 3 , NHCO 2 R 3 , - NH(CO)R 3 , -NH(CO)NHR 3 , and -NH(SO 2 )NHR 3 .
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is selected from the group consisting of -C(O)- R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • G can be -0-R 3 ', -NH-C(O)-R 3 ', -NH-SO 2 -NH-R 3 ' or -NHSO 2 - R 3 ', where R 3 ' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, - C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Re and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is - Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -C 1 -C 8 alkyl, substituted - C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -C3-C12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C3-C12 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - C 12 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 - Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-Rs, where R 5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 - C 12 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-NH-R 5 , where R 5 is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • L is selected from -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, and substituted -C 3 -C 12 cycloalkenyl.
  • A is -C(O)-Rs, where R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • R5 is substituted -Ci-Cg alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 -Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, substituted -C 2 -Cs alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cs alkyl, -C 2 -Cs alkenyl, substituted -Ci-Cs alkyl, or substituted -C 2 -Cs alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 - Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, substituted -C 2 -Cs alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • the present invention relates to a compound of formula VI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Yi-Y 3 are independently selected from CO, CH, NH, N, S and O; and Y 1 -Y 3 can be further substituted when any one OfYi-Y 3 is CH or NH; Y 4 is selected from C, CH and N; and where A, G, L, R 6 , R 7 , V and Z are as previously defined in the embodiment immediately above.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cs alkyl, -C 2 -Cs alkenyl, -C 2 -Cs alkynyl, substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, substituted -C 2 -Cs alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is selected from the group consisting of -C(O)- R 5 , -C(O)-O-R 5 and -C(O)-NH-R 5 , where R 5 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L and Z can be independently selected from Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • G can be -0-R 3 ', -NH-C(O)-R 3 ', -NH-SO 2 -NH-R 3 ' or -NHSO 2 - R 3 ', where R 3 ' is selected from hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, - C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-R 5 or -C(O)-NH-R 5 , where R 5 is - Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted - C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • L is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, substituted -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-Cg alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 - Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 - Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-O-Rs, where R5 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • L is selected from -Ci-Cg alkyl or substituted -Ci-Cg alkyl.
  • Z is selected from -C 2 -Cg alkenyl or substituted -C 2 -Cg alkenyl.
  • G is -NHSO 2 -R 3 ', where R 3 ' is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-NH-R 5 , where R5 is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • L is selected from -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -C 2 -C 8 alkenyl or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 - Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-R 5 , where R 5 is substituted -Ci-C 8 alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • R 5 is substituted -Ci-C 8 alkyl (e.g., substituted methyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2) -NHC(O)-aryl or -NHC(O)-heteroaryl, and optionally (3) one or more other substituents.
  • L is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, -C 2 -Cg alkynyl, substituted -Ci-Cg alkyl, substituted -C 2 -Cg alkenyl, substituted -C 2 -Cg alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • Z is selected from -Ci-Cg alkyl, -C 2 -Cg alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl.
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 - C 8 alkynyl, substituted -Ci-C 8 alkyl, substituted -C 2 -C 8 alkenyl, substituted -C 2 -C 8 alkynyl, -C 3 -Ci 2 cycloalkyl, -C 3 -Ci 2 cycloalkenyl, substituted -C 3 -Ci 2 cycloalkyl, and substituted -C 3 -Ci 2 cycloalkenyl.
  • A is -C(O)-Rs, where R5 is substituted methyl and is substiututed at least with (1) aryl or heteroaryl and (2) -NHC(O)-aryl or -NHC(O)-heteroaryl.
  • L is -Ci-C 8 alkyl or substituted -Ci-C 8 alkyl.
  • Z is selected from -Ci-C 8 alkyl, -C 2 -C 8 alkenyl, substituted -Ci-C 8 alkyl, or substituted -C 2 -C 8 alkenyl.
  • G is -NHSO 2 -R 3 , where R 3 is -C 3 -Ci 2 cycloalkyl or substituted -C 3 -Ci 2 cycloalkyl.
  • Mi is selected from the group consisting of: wherein R 31 and R 32 are independently selected from the group consisting of: a) hydrogen; b) aryl; substituted aryl; c) heteroaryl; substituted heteroaryl; d) -Ci-Cg alkyl, -C 2 -Cg alkenyl, or -C 2 -Cg alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; e) -C 3 -C 12 cycloalkyl, or substituted -C 3 -C 12 cycloalkyl; -C 3 -C 12 cycloalkenyl, or substituted -C 3 -C 12 cycloalkenyl; heterocyclic or substituted heterocyclic; f) -A-R 30 , where A is (CO), (
  • V is absent, or V is O, S, SO, SO 2 , NR50, or
  • R 50 is selected from H, OH, OCH 3 , -0-Ci-C 8 alkyl, -Ci-C 8 alkyl, -0-C 3 -C 8 cycloalkyl, -C 3 -C 8 cycloalkyl, -O- C 3 -C 8 cycloalkenyl; -C 3 -C 8 cycloalkenyl; where q is 1, 2, 3 or 4; and where X and Y are independently selected from the group consisting of:
  • NR 50 (SO 2 )OR 30 NR 50 (SO 2 )NR 30 R 40 ; where R 30 , R 40 and R 50 are as previously defined; alternatively, for formula (I), R 30 and R 40 are taken together with the nitrogen atom to which they are attached to form the group consisting of: heterocyclic, or substituted heterocyclic; heteroaryl, or substituted heteroaryl; M 2 is selected from the group consisting of:
  • R 60 is selected from H, OH, OCH 3 , -0-Ci-C 8 alkyl, -Ci-C 8 alkyl;
  • J is selected from the group consisting of CO, (CO)O, (CO)NR 50 , SO 2 , (SO 2 )O or SO 2 NR 50 ;
  • Rg 0 is selected from the group consisting of: (1) hydrogen;
  • L is selected from the group consisting of:
  • the present invention relates to compound of formula X, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Yet another embodiment of the present invention relates to compound of formula XI, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • the present invention relates to compound of formula XII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Xi and Yi are independently selected from CH and N; R90, R100, Ri 10, and R120 are independently R30; G, J, L, M 2 , R70, and Rso are as previously defined in the embodiment above.
  • the present invention relates to compound of formula XIII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • G, J, L, M 2 , R70, Rso, V, X and Y are as previously defined in the embodiment above.
  • the present invention relates to compound of formula XIV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Xi-X 4 are independently selected from CH and N; Xi-X 4 can be further substituted when it is a CH; where G, J, L, M 2 , R70, Rso, R90, R100 and V are as previously defined in the embodiment above.
  • the present invention relates to compound of formulae XV, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • Y 1 -Y 3 are independently selected from CH, N, NH, S and O; and Y 1 - Y 3 can be further substituted when it is CH or NH; Y 4 is selected from CH and N; where G, J, L, M 2 , R70, Rso, R90, R100 and V are as previously defined.
  • the present invention relates to compound of formula XVI or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • the present invention relates to compound of formula XVII, or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • -C 2 -Cg alkynyl each containing 0, 1 , 2, or 3 heteroatoms selected from O, S or N; i) -C 3 -C 12 cycloalkyl, or -C 3 -Ci 2 cycloalkenyl; j) substituted -C 3 -Ci 2 cycloalkyl, or substituted -C 3 -Ci 2 cycloalkenyl; k) oxo substituted -C 3 -Ci 2 cycloalkyl, or oxo substituted -C 3 -Ci 2 cycloalkenyl; 1) -Q-Ri 03 , where Q is (CO), (CO)O, (CO)NRi 04 , (SO), (SO 2 ),
  • (SO 2 )NRiO 4 ; and Rio 3 and Rio4 are independently selected from the group consisting of: (i) Hydrogen; (ii) aryl; (iii) substituted aryl;
  • Gi is -E-R 103 , where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO), NH(CO)NH, NH(SO 2 )NH or NHSO 2 ;
  • A is selected from the group consisting of R 105 , (CO)Rios, (CO)ORios, (CO)NHRios,
  • RiO 5 is selected from the group consisting of: a) hydrogen b) substituted aryl; c) heteroaryl fused with O, 1, 2, or 3 more group selected from heteroaryl and aryl; d) substituted heteroaryl fused with O, 1, 2 or 3 more group selected from heteroaryl, substituted heteroaryl, aryl and substituted aryl; e) heterocyclic; f) substituted heterocyclic; g) oxo substituted heterocyclic; h) -C 1 -C 8 alkyl, -C 2 -Cs alkenyl, or -C 2 -Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; i) substituted -Ci-Cs alkyl, substituted -C 2 -Cs alkenyl, or substituted -C 2 -Cs alkynyl each containing O, 1, 2, or 3 heteroatoms selected from O, S or N; j)
  • Bi is H or CH 3 ;
  • Li and Zi are independently selected from the group consisting of: (1) hydrogen; (2) aryl;
  • n 0, 1, 2 or 3
  • h 0, 1, 2, or 3.
  • the invention provides intermediate compounds useful in the synthesis of compounds of formulas I-XVII, B and C, selected from the group consisting of: Compounds (I)- (2) of the formula A:
  • Rx , G and W are delineated for each example in TABLE 1 :
  • Representative compounds of the invention are those selected from compounds (3)- (109) of the formula B:
  • Ri and R 2 are taken together with the carbon to which they are attached to form RiR 2 , and RiR 2 , Rx, L, Z and G are delineated for each example in TABLE 2:
  • the present invention features pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • a further embodiment of the present invention includes pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
  • compositions of the present invention are a pharmaceutical composition comprising a combination of two or more compounds of the present invention, or a pharmaceutically acceptable salt, ester, or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical compositions of the present invention may further contain other anti-HCV agents.
  • anti-HCV agents include, but are not limited to, alpha-interferon, beta-interferon, ribavirin, and amantadine.
  • the pharmaceutical compositions of the present invention may further contain other HCV protease inhibitors.
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • inhibitor(s) of other targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject a therapeutically effective amount of the pharmaceutical compounds or compositions of the present invention.
  • the methods can further include administration of an additional therapeutic agent, including another antiviral agent or an anti-HCV agent.
  • the additional agent can be coadministered, concurrently administered or sequentially administered with a compound or pharmaceutical composition of the present invention.
  • the additional agent and the compound of the present invention can be co-formulated in a single dosage form or composition, or prepared in separate dosage forms or compositions.
  • the methods herein can further include the step of identifying that the subject is in need of treatment for hepatitis C infection.
  • the identification can be by subjective (e.g., health care provider determination) or objective (e.g., diagnostic test) means.
  • the present invention also features the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, for the manufacture of a medicament for the treatment of HCV infection.
  • the medicament can also include one or more other anti-HCV agent, such as alpha-interferon, beta- interferon, ribavirin, amantadine, another HCV protease inhibitor, or an HCV polymerase, helicase or internal ribosome entry site inhibitor.
  • aryl refers to a mono- or polycyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • heteroaryl refers to a mono- or polycyclic (e.g. bi-, or tri-cyclic or more), fused or non-fused, aromatic radical or ring having from five to ten ring atoms of which one or more ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from, for example, S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • Ci-Cs alkyl or “C 1 -C 12 alkyl,” as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing from one to eight, or from one and twelve carbon atoms, respectively.
  • Ci-Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals; and examples of C 1 -C 12 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl, decyl, dodecyl radicals.
  • C 2 -Cs alkenyl denotes a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety contains from two to eight carbon atoms and has at least one carbon-carbon double bond.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.
  • C 2 -Cs alkynyl denotes a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety contains from two to eight carbon atoms and has at least one carbon-carbon triple bond.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • Cs-Cg-cycloalkyl or "C3-Ci2-cycloalkyl,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom wherein the carbocyclic ring has from 3 to 8 ring atoms, or from 3 to 12 ring atoms, respectively.
  • C 3 -C 8 -cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C3-C12- cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • Cs-Cg-cycloalkenyl or "C 3 -Ci 2 -cycloalkenyl” as used herein, denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound by the removal of a single hydrogen atom wherein the carbocyclic ring has at least one carbon-carbon double bond and contains from 3 to 8 ring atoms, or from 3 to 12 ring atoms, respectively.
  • Cs-Cs-cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C3-C12- cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • substituted refers to independent replacement of one, two, three or more of hydrogen atoms on a parent moiety with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO 2 , -CN, - NH 2 , protected amino, -NH -C r C 12 -alkyl, -NH -C 2 -C 12 -alkenyl, -NH -C 2 -C 12 - alkenyl, -NH -C 3 -C 12 -cycloalkyl, -NH -aryl, -NH -heteroaryl, -NH - heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C 2 -Ci2-alkenyl
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from -F, -Cl, -Br, -I, - OH, -NO 2 , -CN, or -NH 2 .
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can be replaced by an aliphatic group, an alicyclic group or a heterocyclic group.
  • An "aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • alicyclic denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • heterocyclic refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group fused system, where (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above rings may be fused to a benzene ring, and (v) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, [l,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.
  • Such heterocyclic groups may be further substituted to give substituted heterocyclic.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be divalent or trivalent.
  • alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the formulas herein with proper valency.
  • halo or halogen,” as used herein, refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, /?-nitrobenzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, l,l-dimethyl-2-propenyl, 3 -methyl- 3 -butenyl, allyl, benzyl, para-methoxy
  • Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH 3 ), benzoyl (Bz or -C(O)C 6 H 5 ), and trimethylsilyl (TMS or- Si(CHs) 3 ).
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in T. H. Greene and P. G. M.
  • amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • alkylamino refers to a group having the structure -NH(Ci-Ci 2 alkyl) where C1-C12 alkyl is as previously defined.
  • acyl includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphorous acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
  • protogenic organic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al, Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • General synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations. VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
  • subject refers to an animal.
  • the animal is a mammal. More preferably the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- , or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. Likewise, unless the text states otherwise, a carbon-carbon double bond or carbon-heteroatom double bond depicted herein as cis may be cis, trans, or a mixture of the two in any proportion.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means or by hydrolysis to a compound of Formula I.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • This invention also encompasses pharmaceutical compositions containing, and methods of treating viral infections through administering, pharmaceutically acceptable prodrugs of compounds of the invention.
  • compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxyysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; algin
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • viral infections are treated or prevented in a subject, such as a human, by administering to the subject a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention means a sufficient amount of the compound so as to decrease the viral load in a subject and/or decrease the subject's HCV symptoms.
  • a therapeutically effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of the present invention in such amounts and for such time as is necessary to inhibit viral replication and/or reduce viral load.
  • the term “inhibitory amount” means a sufficient amount to inhibit viral replication and/or decrease the hepatitis C viral load in a biological sample.
  • biological sample(s) as used herein means a substance of biological origin intended for administration to a subject. Examples of biological samples include, but are not limited to blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells.
  • Another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.
  • Boc for te/t-butoxycarbonyl
  • Bz for benzoyl
  • CDI for carbonyldiimidazole
  • dba for dibenzylidene acetone
  • DMSO dimethyl sulfoxide
  • dppb diphenylphosphino butane
  • EtOAc ethyl acetate
  • HATU 2-(7-Aza- 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate; iPrOH for isopropanol;
  • NaHMDS for sodium bis(trimethylsilyl)amide
  • NMO for N-methylmorpholine N-oxide
  • POPd for dihydrogen dichlorobis(di-tert-butylphosphino)palladium(II); TBAHS for tetrabutyl ammonium hydrogen sulfate;
  • TPP for triphenylphosphine
  • Tris for Tris(hydroxymethyl)aminomethane
  • DIBAL-H for diisobutylaluminum hydride
  • DIEA for diisopropyl ethylamine
  • KHMDS is potassium bis(trimethylsilyl) amide
  • RT-PCR for reverse transcription-polymerase chain reaction
  • TEA for triethyl amine
  • Scheme 1 describes the synthesis of intermediate (1-6).
  • the acyclic peptide precursor (1-6) was synthesized from Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1.
  • Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1.
  • Scheme 1 describes the synthesis of intermediate (1-6).
  • the acyclic peptide precursor (1-6) was synthesized from Boc-L-tert-leucine (1-1) and cis-L- hydroxyproline methyl ester (1-2) via 3 steps set forth generally in Scheme 1.
  • intermediate (2-2) can also be made by converting hydroxy intermediate (1-6) to a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide; followed with the deprotection of the phthalimide moiety with ammonia or hydrazine.
  • Oximes (2-3) can be prepared by treating hydroxy amine with appropriate aldehyde or ketone optionally in the presence of an acid. Subsequent removal of the acid protecting group furnishes compounds of formula (2-4).
  • a thorough discussion of solvents and conditions for protecting the acid group can be found in T. W. Greene and P. GM. Wuts, Protective Groups in Organic Synthesis, 3 rd ed., John Wiley & Son, Inc, 1999.
  • the Scheme 3 describes the alternative methods to synthesize formula (3-2).
  • the intermediates (3-1) can be made directly through (1-6) and oximes using Mitsunobu conditions. Or, intermediate (3-1) can also be made through SN2 replacement of activated hydroxyl group by converting hydroxy intermediate (1-6) to a suitable leaving group such as, but not limited to OMs, OTs, OTf, bromide, or iodide. Subsequent removal of the acid protecting group furnishes compounds of formula (3-2).
  • Scheme 4 [
  • Scheme 4 illustrates the modification of the N-terminal and C-terminal of the acyclic peptide (4-1).
  • Deprotection of the Boc moiety with an acid yields compounds of formula (4-2).
  • the amino moiety of formula (4-2) can be alkylated or acylated with appropriate alkyl halide or acyl groups to give compounds of formula (4-3).
  • Compounds of formula (4-3) can be hydrolyzed with base such as lithium hydroxide to free up the acid moiety of formula (4-4). Subsequent activation of the acid moiety followed by treatment with appropriate acyl or sulfonyl groups to provide compounds of formula (4-5).
  • step Ib To a solution of the free acid obtained from step Ib (1.5g) in 5 ml DMF, D- ⁇ -vinyl cyclopropane amino acid ethyl ester (1.Og), DIEA (3.8ml) and HATU (2.15g) were added. The coupling was carried out at 0 0 C over a period of 5 hours. The reaction mixture was diluted with 200 mL EtOAc, and followed by washing with 5% citric acid 2x 20 ml, water 2x20 ml, IM NaHCO 3 4x20 ml and brine 2x10 ml, respectively. The organic phase was dried over anhydrous Na 2 SO 4 and then evaporated.
  • Step If To a solution of the compound from step Ie (1.22mmol) in DCM was added DIEA (2.2ml) and cyclopentylchloroformate (3eq) at O 0 C. The mixture was stirred for 1.5h at room temperature. The reaction mixture was extracted with EtOAc. The organic extracts were washed with NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by silica gel chromatography to give 850mg of desired product.
  • Step 3a is attached to Step 3a.
  • Step 3b To a solution of the compound from step 3a in THF/MeOH was added INLiOH. The reaction mixture was stirred overnight at room temperature. After acidified with INHCl, the resulting mixture was extracted with EtOAc. The organic extracts were washed with water and concentrated. The residue was purified by preparative HPLC to give desired product 1 and product 2.
  • 13C (CD 3 OD): 5174.0, 172.0, 169.5, 157.4, 153.6, 141.8, 140.5, 135.2, 133.1, 131.3, 130.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.9, 117.4, 82.8, 77.8, 59.8, 59.4, 54.1, 53.6, 41.3, 35.1, 34.8, 34.4, 32.5, 32.3, 30.9, 25.8, 23.3, 22.5, 5.6, 5.3.
  • 13C (CD3OD): 5174.0, 171.9, 170.4, 157.5, 153.6, 141.8, 140.5, 135.2, 131.3, 130.2, 129.2, 128.2, 127.9, 121.6, 119.9, 82.8, 77.8, 59.8, 59.4, 54.1, 39.1, 35.1, 34.5, 34.4, 32.5, 32.3, 30.9, 25.8, 23.3, 22.6, 19.6, 12.7, 5.5, 5.1.
  • Step 12a is cyclopropyl
  • 13C(CDCB) 5172.9, 172.3, 168.5, 156.1, 153.6, 141.5, 140.3, 135.2, 132.5, 131.2, 130.2, 129.4, 128.4, 128.0, 121.9, 119.8, 118.5, 82.2, 73.6, 59.8, 59.1, 53.8, 41.8, 35.6, 35.4, 34.0, 31.9, 31.8, 31.2, 26.4, 26.3, 25.3, 23.9, 23.6, 22.5, 6.3, 6.2, 6.1.
  • Example 20 to Example 109 are made following the procedures described in Examples 1, 3, 4 or 12.
  • step HOd The compound from step HOd was hydro lyzed with LiOH in THF/MeOH/H 2 O (2:1 :1) overnight.
  • the reaction mixture was acidified with IN HCl, extracted with 3 mL EtOAc, and washed with brine 2x1 ml.
  • the organic phase was dried over anhydrous Na 2 SO 4 and then evaporated to give desired acid (660mg) without further purification.
  • 13C (CD3OD): 5174.1, 172.9, 170.5, 156.7, 153.5, 141.8, 140.5, 135.2, 130.2, 129.1, 128.3, 127.9, 121.6, 119.9, 119.8, 82.9, 79.1, 60.0, 58.2, 53.3, 39.1, 34.2, 30.8, 30.5, 27.3, 23.0, 19.4, 18.6, 17.8, 12.7, 5.5, 5.0.
  • Step 112b To the solution of the compound from step 112a in 2ml DCM was added DIEA
  • 13C (CD3OD): 5174.1, 172.9, 170.5, 157.4, 153.6, 141.7, 140.5, 135.3, 131.3, 130.2, 129.2, 128.3, 127.9, 121.6, 119.8, 82.9, 77.7, 59.9, 58.6, 53.3, 39.1, 34.2, 32.4, 32.3, 30.8, 30.4, 23.2, 22.9, 19.4, 18.6, 17.8, 12.7, 5.5, 5.0.
  • Step 116a
  • Step 118a
  • Step 122a
  • 13C(CDCB) ⁇ 173.0, 172.5, 167.9, 156.7, 153.7, 141.5, 140.3, 139.0, 135.1, 135.0, 133.5, 132.1, 131.3, 130.2, 129.4, 128.3, 128.0, 126.8, 121.8, 119.8, 118.4, 82.1, 77.2, 61.2, 59.9, 59.3, 58.6, 53.9, 50.7, 41.6, 35.6, 34.1, 16.5, 22.6, 18.1, 14.3.
  • Example 129 Compound of formula C, wherein Rx .OrV .w.
  • Example 126 The title compound was prepared with compound from Example 126 with 4- morpholinecarbonyl chloride via the similar conditions described in Example 127.
  • Example 133b To a flask containing the compound from Example 133b (200mg) was added 4N HCl/dioxane (8ml). The resulting mixture was stirred for 1 hr at room temperature. The mixture was then concentrated to give desired product without further purification.
  • step 133d The compound from step 133d was hydro lyzed with LiOH in THF/MeOH/H 2 O (2:1 :1) overnight.
  • the reaction mixture was acidified with IN HCl, extracted with 5 mL EtOAc, and washed with brine 2x1 ml.
  • the organic phase was dried over anhydrous Na 2 SO 4 and then evaporated to give desired acid without further purification.
  • MS (ESI): m/z 522.15 [M+H].
  • Example 136 Compound of formula C, wherein Rx .W-
  • Step 136a To a solution of D- ⁇ -vinyl cyclopropane amino acid (2.8g) in DCM (30ml) was added CDI (2.8g). The reaction mixture was stirred at 4O 0 C for Ih and then added cyclopropylsulfonamide 2.98g and DBU 3.69ml. The reaction mixture was stirred overnight at 4O 0 C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was added 4N HCl/dioxne. The reaction mixture was stirred at room temperature for Ih. The mixture was then concentrated to give desired product without further purification.
  • Example 137 Compound of formula C, wherein Rx ⁇ OJy
  • Example 139 Compound of formula C, wherein Rx ⁇ OJy
  • Example 142 The title compound was prepared with compound from Example 126 with 3,3- dimethylbutyraldehyde via the similar conditions described in Example 142.
  • Example 146 Compound of formula C, wherein Rx -Cr-Yi . w-
  • Example 127 The title compound was prepared with compound from Example 126 with cyclobutanemethylchloroformate via the similar conditions described in Example 127.
  • Example 142 The title compound was prepared with compound from Example 126 with phenylacetaldehyde via the similar conditions described in Example 142.
  • Example 142 The title compound was prepared with compound from Example 126 with glyoxylic acid via the similar conditions described in Example 142.
  • Example 142 The title compound was prepared with compound from Example 126 with cyclohexanone via the similar conditions described in Example 142.
  • Example 165 Compound of formula C, wherein Rx - ⁇ i .l .w-
  • Example 142 The title compound was prepared with compound from Example 126 with 1- adamantane-ethylaldehyde via the similar conditions described in Example 142.
  • Example 166 Compound of formula C, wherein Rx -l&y. .w-
  • Example 137 The title compound was prepared with compound from Example 136 with T- methoxybiphenyl-2-aldehyde via the similar conditions described in Example 137.
  • Example 184 Compound of formula C, wherein Rx ⁇ /. .W
  • Example 185 Compound of formula C, wherein Rx . . >
  • Example 184 The title compound was prepared with compound of Example 184 with via the similar conditions described in Example 114.
  • 13C (CDC13): 5172.9, 172.2, 169.2, 156.6, 153.9, 141.8, 140.5, 135.3, 132.6, 131.5, 130.5, 129.6, 128.7, 128.2, 122.1, 120.1, 118.9, 82.3, 78.5, 69.7, 60.3, 56.4, 53.5, 41.1, 36.0, 34.7, 33.0, 32.7, 31.4, 24.5, 23.8, 23.7, 20.2, 6.5, 6.3.
  • 13C (CDC13): 5172.4, 169.3, 157.1, 153.9, 148.5, 141.7, 140.5, 135.4, 132.6, 131.4, 130.5, 130.4, 129.7, 128.9, 128.2, 122.1, 120.1, 120.0, 118.8, 83.8, 82.4, 78.2, 72.1, 60.0, 57.7, 53.5, 41.0, 36.1, 34.9, 33.1, 32.6, 32.5, 31.4, 27.2, 26.5, 24.6, 23.8, 23.7, 23.6, 6.4, 6.3.
  • Example 196 The title compound was prepared with compound of Example 196 with bezoic acid via the similar conditions described in Example 144.
  • Example 126 The title compound was prepared with compound of Example 126 with cyclohexylisocynate via the similar conditions described in Example 127.
  • Example 216 Compound of formula C, wherein Rx ⁇ OJy
  • Example 137 The title compound was prepared with compound from Example 136 with benzaldehyde via the similar conditions described in Example 137.
  • the compound was prepared using (2S,4S)-l-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid and (lR,2S)-ethyl l-amino-2- vinylcyclopropanecarboxylate via conditions similar to those described in step Ic of Example 1.
  • the compound was prepared using the compound from step 226a of example 226 and 2,7-dibromo-9H-fluoren-9-one oxime via conditions similar to those described in step 10b of Example 10.
  • the compound was prepared with the compound from step 226b of example 226 via conditions similar to those described in step Ie of Example 1.
  • reaction mixture was stirred at 40 0 C for 1 h and then cyclopropylsulfonamide and DBU were added.
  • the reaction mixture was stirred at 40 0 C for 2 h.
  • the reaction mixture was diluted with ethyl acetate and washed with IM HCl, brine, dried over anhydrous MgSO 4 , filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product.
  • a DABCYL and an EDANS group are attached to opposite ends of a short peptide. Quenching of the EDANS fluorescence by the DABCYL group is relieved upon proteolytic cleavage. Fluorescence is measured with a Molecular Devices Fluoromax (or equivalent) using an excitation wavelength of 355 nm and an emission wavelength of 485 nm.
  • the assay is run in Corning white half-area 96-well plates (VWR 29444-312 [Corning 3693]) with full-length NS3 HCV protease Ib tethered with NS4A co factor (final enzyme concentration 1 to 15 nM).
  • the assay buffer is complemented with 10 ⁇ M NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW 1424.8).
  • RET Sl (Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser- LyS-(DABCYL)-NH 2 , AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate.
  • the assay buffer contains 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mM BME. The enzyme reaction is followed over a 30 minutes time course at room temperature in the absence and presence of inhibitors.
  • HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu- Met-Glu-Glu-Cys-OH, [-20 0 C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac- Asp-Glu-Dif-Cha-Cys-OH, are used as reference compounds.
  • HCV Cell Based Assay Quantification of HCV replicon RNA (HCV Cell Based Assay) is accomplished using the Huh 11-7 cell line (Lohmann, et al Science 285:110-113, 1999). Cells are seeded at 4x10 3 cells/well in 96 well plates and fed media containing DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and non-essential amino acids. Cells are incubated in a 7.5% CO 2 incubator at 37 0 C. At the end of the incubation period, total RNA is extracted and purified from cells using Ambion RNAqueous 96 Kit (Catalog No. AMI 812).
  • primers specific for HCV mediate both the reverse transcription of the HCV RNA and the amplification of the cDNA by polymerase chain reaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog no. 4309169).
  • PCR polymerase chain reaction
  • the nucleotide sequences of the RT-PCR primers, which are located in the NS5B region of the HCV genome, are the following: HCV Forward primer "RBNS5bfor"
  • Detection of the RT-PCR product is accomplished using the Applied Biosystems (ABI) Prism 7500 Sequence Detection System (SDS) that detects the fluorescence that is emitted when the probe, which is labeled with a fluorescence reporter dye and a quencher dye, is degraded during the PCR reaction.
  • SDS Sequence Detection System
  • the increase in the amount of fluorescence is measured during each cycle of PCR and reflects the increasing amount of RT-PCR product.
  • quantification is based on the threshold cycle, where the amplification plot crosses a defined fluorescence threshold. Comparison of the threshold cycles of the sample with a known standard provides a highly sensitive measure of relative template concentration in different samples (ABI User Bulletin #2 December 11, 1997).
  • the data is analyzed using the ABI SDS program version 1.7.
  • the relative template concentration can be converted to RNA copy numbers by employing a standard curve of HCV RNA standards with known copy number (ABI User Bulletin #2 December 11, 1997).
  • the RT reaction is performed at 48 0 C for 30 minutes followed by PCR.
  • Sequence Detection System are: one cycle at 95 0 C, 10 minutes followed by 40 cycles each of which include one incubation at 95 0 C for 15 seconds and a second incubation for 60 0 C for 1 minute.
  • RNA, RT-PCR is performed on the cellular messenger RNA glyceraldehyde-3- phosphate dehydrogenase (GAPDH).
  • GAPDH messenger RNA glyceraldehyde-3- phosphate dehydrogenase
  • the GAPDH copy number is very stable in the cell lines used.
  • GAPDH RT-PCR is performed on the same RNA sample from which the HCV copy number is determined.
  • the GAPDH primers and probes are contained in the ABI Pre-Developed TaqMan Assay Kit (catalog no. 4310884E).
  • the ratio of HCV/GAPDH RNA is used to calculate the activity of compounds evaluated for inhibition of HCV RNA replication.
  • Activity of compounds as inhibitors of HCV replication (Cell based Assay) in replicon containing Huh-7 cell lines.
  • the effect of a specific anti-viral compound on HCV replicon RNA levels in Huh-1 l-7cells is determined by comparing the amount of HCV RNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposed to compound versus cells exposed to the DMSO vehicle (negative control).
  • cells are seeded at 4x 10 3 cells/well in a 96 well plate and are incubated either with: 1) media containing 1% DMSO (0% inhibition control), or 2) media/1 %DMS0 containing a fixed concentration of compound.
  • Cl the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0% inhibition control (media/1 %DMSO).
  • the dose-response curve of the inhibitor is generated by adding compound in serial, three-fold dilutions over three logs to wells starting with the highest concentration of a specific compound at 1.5 uM and ending with the lowest concentration of 0.23 nM. Further dilution series (500 nM to 0.08 nM for example) is performed if the EC50 value is not positioned well on the curve.
  • EC50 is determined with the IDBS Activity Base program "XL Fit" using a 4-paramater, non-linear regression fit (model # 205 in version 4.2.1, build 16).
  • representative compounds of the present invention are found to have HCV replication inhibitory activity and HCV NS3 protease inhibitory activity.
  • representative compounds of formulae III and IV as depicted above, showed significant HCV replication inhibitory activity. These compounds were also effective in inhibiting HCV NS3 proteases of different HCV genotypes including genotypes 1, 2, 3 and 4.
  • representative compounds in the preferred examples of formulae III and IV showed EC50s in the range of from less than 0.2 nM to about 10 nM using cell-based replicon assays.
  • Representative compounds of these preferred examples also inhibited HCV NS3 proteases of different HCV genotypes, such as genotypes Ia, Ib, 2a, and 4a, with IC50s in the range of from less than 0.2 nM to about 50 nM.

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Abstract

La présente invention concerne des composés répondant à la formule I ou des sels, des esters, ou des promédicaments pharmaceutiquement acceptables de ces composés, qui inhibent l'activité de la sérine protéase, en particulier l'activité de la protéase NS3-NS4A du virus de l'hépatite C (VHC). En conséquence, les composés de la présente invention interfèrent avec le cycle de vie du virus de l'hépatite C et ils se révèlent également utiles en tant qu'agents antiviraux. La présente invention concerne en outre des compositions pharmaceutiques contenant les composés susmentionnés, destinés à être administrés à un sujet souffrant d'une infection par le VHC. L'invention concerne également des procédés de traitement d'un sujet atteint d'une infection par le VHC par l'administration d'une composition pharmaceutique contenant les composés de la présente invention.
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WO2008070358A3 (fr) * 2006-11-16 2008-11-06 Phenomix Corp Inhibiteurs de la sérine protéase de l'hépatite c et utilisations de ceux-ci
US8193346B2 (en) 2007-12-06 2012-06-05 Enanta Pharmaceuticals, Inc. Process for making macrocyclic oximyl hepatitis C protease inhibitors
US8222203B2 (en) 2007-12-14 2012-07-17 Enanta Pharmaceuticals, Inc. Macrocyclic oximyl hepatitis C serine protease inhibitors
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US8283309B2 (en) 2007-12-20 2012-10-09 Enanta Pharmaceuticals, Inc. Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors
US8361958B2 (en) 2007-12-05 2013-01-29 Enanta Pharmaceuticals, Inc. Oximyl HCV serine protease inhibitors
US8372802B2 (en) 2008-03-20 2013-02-12 Enanta Pharmaceuticals, Inc. Fluorinated macrocyclic compounds as hepatitis C virus inhibitors
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WO2013173392A1 (fr) 2012-05-15 2013-11-21 Concortis Biosystems, Corp Conjugués de médicament, procédés de conjugaison et utilisation de ceux-ci
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US9284307B2 (en) 2009-08-05 2016-03-15 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors
US9353100B2 (en) 2011-02-10 2016-05-31 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections
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US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives

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WO2008070358A3 (fr) * 2006-11-16 2008-11-06 Phenomix Corp Inhibiteurs de la sérine protéase de l'hépatite c et utilisations de ceux-ci
US8426360B2 (en) 2007-11-13 2013-04-23 Enanta Pharmaceuticals, Inc. Carbocyclic oxime hepatitis C virus serine protease inhibitors
US8268777B2 (en) 2007-12-05 2012-09-18 Enanta Pharmaceuticals, Inc. Oximyl macrocyclic derivatives
US8361958B2 (en) 2007-12-05 2013-01-29 Enanta Pharmaceuticals, Inc. Oximyl HCV serine protease inhibitors
US8193346B2 (en) 2007-12-06 2012-06-05 Enanta Pharmaceuticals, Inc. Process for making macrocyclic oximyl hepatitis C protease inhibitors
US8222203B2 (en) 2007-12-14 2012-07-17 Enanta Pharmaceuticals, Inc. Macrocyclic oximyl hepatitis C serine protease inhibitors
US8283309B2 (en) 2007-12-20 2012-10-09 Enanta Pharmaceuticals, Inc. Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors
US8372802B2 (en) 2008-03-20 2013-02-12 Enanta Pharmaceuticals, Inc. Fluorinated macrocyclic compounds as hepatitis C virus inhibitors
US8993595B2 (en) 2009-04-08 2015-03-31 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors
US9284307B2 (en) 2009-08-05 2016-03-15 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors
US9353100B2 (en) 2011-02-10 2016-05-31 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections
WO2013173393A1 (fr) 2012-05-15 2013-11-21 Concortis Biosystems, Corp Conjugués médicamenteux, procédés de conjugaison et utilisations de ceux-ci
WO2013173391A1 (fr) 2012-05-15 2013-11-21 Concortis Biosystems, Corp Conjugués de médicament, procédés de conjugaison, et utilisations associées
WO2013173392A1 (fr) 2012-05-15 2013-11-21 Concortis Biosystems, Corp Conjugués de médicament, procédés de conjugaison et utilisation de ceux-ci
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EP3925627A1 (fr) 2012-05-15 2021-12-22 Concortis Biosystems, Corp Conjugués de médicaments et leurs utilisations
EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11866422B2 (en) 2016-06-21 2024-01-09 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
CN110904121A (zh) * 2019-12-17 2020-03-24 南京农业大学 易感基因sr30在改良农作物抗性中的应用

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